It’s a long, long jump from promising results in animal studies to anything like a useful treatment for humans, but researchers are making progress toward genetic treatments for a number of diseases. Now, a research team at the University of Florida is reporting that they have used a form of gene therapy to ward off high blood pressure in rats. Not only does the therapy permanently alter the animals’ DNA blueprint, but it also prevents the animals’ offspring from inheriting the disorder.
The advance represents the first time researchers have been able to protect future generations through gene therapy for any condition, says Dr. Mohan K. Raizada, a molecular physiologist who was one of the lead investigators. Other studies have shown random bits of inserted genes can be passed on but with no therapeutic effect.
The new approach involves using special genes to block the action of a sometimes-harmful hormone, angiotensin, which causes blood vessels to narrow, increasing blood pressure. The findings of Dr. Raizada and his colleagues will be published in Circulation Research: Journal of the American Heart Association.
Passing Along Benefits
“The neat part of this study is we’re able to show both the effects on high blood pressure as well as on the organs involved in the control of blood pressure,” says Raizada. “We have shown that this form of gene therapy not only prevents these animals from developing high blood pressure, but also prevents a lot of other types of pathophysiological changes in the heart, the kidney, and the arteries.”
What’s more, after studying two subsequent generations of rats, researchers discovered the beneficial changes were passed on. Those offspring should have had high blood pressure but didn’t, says Dr. Craig H. Gelband, a vascular biologist, also with the university, who worked on the study with Raizada. They collaborated with Michael J. Katovich, in the university’s College of Pharmacy. The project was funded by the National Institutes of Health and the American Heart Association’s Florida affiliate.
How They Did It
The hormone responsible for regulating blood pressure, angiotensin, acts at specialized sites known as receptors, located on the surface of cells. During their study, the researchers rewrote the genetic message that typically orchestrates the creation of these sites. They then packaged the genetic material into a virus modified so it wouldn’t cause illness and injected it into the rats. The virus transported the genetic material into the rats’ cells, instructing them to halt production of the hormone’s receptor sites.
Gelband notes that unlike most other viruses tested in gene therapy, the one his team used appears to act differently once it enters a cell’s nucleus.”
“We’ve shown that our vehicle for the gene therapy, a retrovirus, actually integrates into the animals’ DNA, and this may be the reason why it gets passed on to the next generations,” Gelband says.
Real-World Application Far Off
“For human application now, this research is certainly not applicable,” says Dr. A. J. Marian, assistant professor of medicine in the Baylor College of Medicine in Houston, who has studied genetic treatments for cardiovascular problems. “There are a number of leaps that would have to happen before this could have broad application.”
Dr. Marian says that in humans, hypertension is multifactorial, and that there are a number of genes likely to be involved.
“This is certainly exciting work to show that the genetic modification was inheritable,” he says. “It also is interesting that it shows that these genes do have control of hypertension, but the concept that you can pass this protection among generations of human populations is not realistic at this point.”
However, Dr. Marian says the first real-world applications of genetic treatments probably will come in the next 5 years for cardiovascular diseases.
“Our observations are very exciting in the sense that for the first time there is a possibility of permanent control of high blood pressure involving gene therapy,” says Raizada. “Where that leads to as far as human therapy is concerned is far away. We have many hurdles to jump. For example, our studies have shown we can prevent the development of high blood pressure. But in humans, there are no gene markers to define that a person is going to develop high blood pressure. The key would be to find therapies that would reverse high blood pressure once it has been established.”
To date, gene therapy in humans has been limited to trying to correct existing disease in a way that does not permanently alter a person’s DNA makeup. Raizada notes that before US policy would ever change to allow such studies in people, a wide range of scientists, ethicists, and public-policy specialists would debate the issue, taking into account the implications of changing patterns of heredity.
“We as scientists have got to be very careful,” Raizada says. “What are the physiological consequences? We must not predispose ourselves to thinking there are no side effects to permanent changes, and we should always guard for that.”
The Reality Of High Blood Pressure
An estimated 50 million Americans battle high blood pressure, according to the national Centers for Disease Control and Prevention. The condition affects almost all the body’s vital organs, particularly the heart and kidneys, changing their structure and altering their ability to function properly. It is a major risk factor for stroke, hardening of the arteries, heart failure, heart disease, and kidney damage. Medication controls high blood pressure in many patients, but it can sometimes cause adverse effects such as persistent cough or even low blood pressure.
Article by: John Casey, Medical Writer